Lipoxygenases are a family of iron-containing enzymes that act as catalysts of the oxidation reaction of polyunsaturated fatty acids or other alkenes. Among them, the 5-lipoxygenase (also called 5-LO) catalyzes the oxygenation of arachidonic acid (AA) for providing leukotrienes which are a group of lipid inflammation mediators. Consequently, 5-LO is involved in various diseases, especially, in inflammatory diseases.
Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. This chronic inflammation causes an increase in airway hyperresponsiveness due to certain factors such as allergens, tobacco smoke, chemicals, pollution or some strong emotions.
According to the World Health Organization, asthma affects 235 million people and is characterized by recurrent episodes of wheezing, breathlessness chest tightness and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneous or with the treatment. The severity and frequency of such recurrent episodes may vary from one person to another. However, an appropriate management of the disease can control the troubles and enable to ensure a good quality of life to patients.
To date, different types of treatment are available depending on the degree of severity of the disease in the patient and whether it is a treatment to relieve (in the case of a crisis) or to prevent (background treatment). These treatments are mainly based on decreasing local hyper reactivity of bronchi and/or inflammation.
Biochemical markers of inflammation are known in the art. The presence of elevated levels of these markers has been shown to be associated with the development of inflammatory diseases.
In the case of asthma, the crucial involvement of 5-lipoxygenase (or 5-LO) in mediating disease symptoms is known. The 5-LO catalyzes the conversion of arachidonic acid (AA) into leukotrienes A4 (LTA4) (See FIG. 1). Then, depending on the cell type and the enzymes present, unstable LTA4 can be converted either into leukotriene B4 (LTB4) or into leukotriene comprising a cysteine moiety (CysLT): LTC4, LTD4 and LTE4. CysLT play a prominent role in asthma. Indeed, they were identified as potent mediators of bronchoconstriction and hypersensitivity reactions. LTB4 is a chemotactic agent and promotes inflammation.
To date, few therapeutic agents have been authorized by the FDA or other health authorities as efficient anti-asthmatic drugs; especially by acting through the 5-LO mechanism as described above.
Montelukast (SINGULAIR®) and zafirlukast (ACCOLATE®) are both leukotriene receptor antagonists which inhibit the activity of specific leukotrienes. However, they do not allow acting on the 5-LO and in particular, they do not allow inhibiting leukotriene synthesis.
Zileuton (ZYFLO®) is an orally active inhibitor of 5-LO (both on activity and on 5-LO product formation) acting by an iron-chelating mechanism.

Due to its unfavorable pharmacokinetics (short half-life time), Zileuton-based treatment requires the intake of 600 mg four times a day. This elevated daily amount of drug induces 1) significant side effects such as hepatic issues and neuropsychiatric disorders and 2) contributes to the expensiveness of the treatment.
Thus, in view of the disadvantages as described above, there is a need for providing new treatments for asthma to overcome the drawbacks described above. Especially, there is a need for providing cheaper treatment while enhancing bioavailability for the comfort of the patient without side effects.
There is also a need to provide new compounds allowing the efficient inhibition of 5-LO and subsequently of the production of leukotrienes.
WO2006/093547 (Zhang et al.) reports the inhibition of lipoxygenases by chromanol compounds and their use as therapeutic agents for the treatment of apoptosis of cancer cells.
WO2005/013911 (Sen et al.) reports a method for inhibiting the 12-lipoxygenase in a patient in need thereof, comprising the administration of an efficient amount of tocotrienols.
Reddanna et al. (“Inhibition of 5-lipoxygenase by vitamin E”, FEBS Letters, Vol. 193, N° 1, November 1985, pages 39-43) reports the irreversible and non-competitive inhibition of the 5-LO by vitamin E composed of a set of 8 molecules: 4 tocopherols (α, β, γ, δ) and 4 tocotrienols (α, β, γ, δ), whose structures are presented as below:
   Tocopherol    Tocotrienol CompoundR1R2R3Alpha (α)CH3CH3CH3Beta (β)CH3HCH3Gamma (γ)HCH3CH3Delta (δ)HHCH3
WO00/72862 (Nawar et al.) reports an oil extract of cranberry comprising tocopherols and tocotrienols and suggests its use for the treatment or prevention of conditions associated with the activity of 5-LO.
WO2010/033687 (Gibbs et al.) reports long-chain carboxychromanol compounds comprising a carboxy group at its terminal as useful for treating conditions associated with the need to inhibit the activity of cyclooxygenases or lipoxygenases.
To the Applicant's knowledge, the closest prior art, disclosing δ-garcinoic acid for 5-LO, is US2015/0073044. However, δ-garcinoic acid is not efficient enough to achieve therapeutical purposes; especially, in dermatological and/or chronic airways diseases.
The goal of this invention is providing new compounds allowing inhibiting neutrophil 5-LO product formation (leukotriene formation) in addition to the inhibition of the activity of the 5-LO. None of prior art documents provide compounds allowing inhibition of neutrophil 5-LO product formation (leukotriene formation) with an efficient bioavailability in the organism of the patient treated for 5-LO related diseases. Especially, none of the cited prior art provides therapeutic compounds allowing achievement of efficient plasmatic concentration in a patient treated for chronic airways disorders and/or dermatological diseases.
Surprisingly, the Applicant has highlighted that tocotrienol derivatives inhibit the 5-lipoxygenase via another binding site than that of the natural substrate, the arachidonic acid. This new way provides reversible and noncompetitive inhibitors of both the 5-LO activity and of 5-LO product formation, allowing reducing side effects of treatment.